TY - JOUR
T1 - Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1
AU - Isokawa, Masashi
AU - Sassa, Takayuki
AU - Hattori, Satoko
AU - Miyakawa, Tsuyoshi
AU - Kihara, Akio
N1 - Funding Information:
This work was supported by the Advanced Research and Development Programs for Medical Innovation (AMED‐CREST) Grant Number JP19gm0910002h0005 (to AK) from the Japan Agency for Medical Research and Development (AMED), by a Grant‐in‐Aid for Scientific Research on Innovative Areas “Platform of Advanced Animal Model Support” Grant number 16H06276 (to TM) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and by JSPS KAKENHI Grant Numbers JP18H03976 (to AK), JP18H04664 (to AK), and JP16K08220 (to TS) from the Japan Society for the Promotion of Science (JSPS). Behavioral analysis was carried out at the Institute for Comprehensive Medical Science, Fujita Health University (Joint Usage/Research Center for Genes, Brain and Behavior, accredited by MEXT).
Funding Information:
This work was supported by the Advanced Research and Development Programs for Medical Innovation (AMED-CREST) Grant Number JP19gm0910002h0005 (to AK) from the Japan Agency for Medical Research and Development (AMED), by a Grant-in-Aid for Scientific Research on Innovative Areas “Platform of Advanced Animal Model Support” Grant number 16H06276 (to TM) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and by JSPS KAKENHI Grant Numbers JP18H03976 (to AK), JP18H04664 (to AK), and JP16K08220 (to TS) from the Japan Society for the Promotion of Science (JSPS). Behavioral analysis was carried out at the Institute for Comprehensive Medical Science, Fujita Health University (Joint Usage/Research Center for Genes, Brain and Behavior, accredited by MEXT).
Publisher Copyright:
© 2019 The Authors.
PY - 2019/12
Y1 - 2019/12
N2 - Very-long-chain fatty acids, with a chain length of >C20, are abundant in myelin sphingolipids. Recently, a de novo mutation in the ELOVL1 gene, which encodes fatty acid elongase, was identified in patients with neurocutaneous disorders involving skin ichthyosis and multiple neurological abnormalities, including hypomyelination, spastic paraplegia, and high-frequency deafness. However, the consequences of ELOVL1 deficiency for lipid composition and detailed pathological changes in the brain remain unclear. Here, we analyzed Elovl1 mutant mice as a model of human ELOVL1 deficiency. The mice exhibited a decreased postnatal survival rate, and some died of startle epilepsy. The acyl chain length of sphingolipids such as galactosylceramides, sulfatides, sphingomyelins, and ceramides in the brains of these mice was markedly shortened. Moreover, the mice exhibited reduced levels of galactosylceramides, which are important for myelin formation and stability. Electron microscope analysis of the corpus callosum in Elovl1 mutant mice revealed modest hypomyelination, especially in large-diameter axons. Furthermore, behavioral testing of the mice revealed deficits such as poorer motor coordination and reduced acoustic startle response to high-intensity stimulus. These findings provide clues to the molecular mechanism of the neurological symptoms of patients with the ELOVL1 mutation.
AB - Very-long-chain fatty acids, with a chain length of >C20, are abundant in myelin sphingolipids. Recently, a de novo mutation in the ELOVL1 gene, which encodes fatty acid elongase, was identified in patients with neurocutaneous disorders involving skin ichthyosis and multiple neurological abnormalities, including hypomyelination, spastic paraplegia, and high-frequency deafness. However, the consequences of ELOVL1 deficiency for lipid composition and detailed pathological changes in the brain remain unclear. Here, we analyzed Elovl1 mutant mice as a model of human ELOVL1 deficiency. The mice exhibited a decreased postnatal survival rate, and some died of startle epilepsy. The acyl chain length of sphingolipids such as galactosylceramides, sulfatides, sphingomyelins, and ceramides in the brains of these mice was markedly shortened. Moreover, the mice exhibited reduced levels of galactosylceramides, which are important for myelin formation and stability. Electron microscope analysis of the corpus callosum in Elovl1 mutant mice revealed modest hypomyelination, especially in large-diameter axons. Furthermore, behavioral testing of the mice revealed deficits such as poorer motor coordination and reduced acoustic startle response to high-intensity stimulus. These findings provide clues to the molecular mechanism of the neurological symptoms of patients with the ELOVL1 mutation.
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U2 - 10.1096/fba.2019-00067
DO - 10.1096/fba.2019-00067
M3 - Article
AN - SCOPUS:85091073639
VL - 1
SP - 747
EP - 759
JO - FASEB BioAdvances
JF - FASEB BioAdvances
SN - 2573-9832
IS - 12
ER -